Alkamine esters of cyclopentylalkylacetic acids



Patented Jan. E8531 UNITED STATES PATENT OFFICE ALKAMINE ESTERS OF CYCLOPENTYL- ALKYLACETIC ACIDS No Drawing. Application August 10, 1948, Serial No. 43,542

9 Claims. 1

This invention relates to aminoalkyl esters of cyclopentylalkylacetic acids and to thereapeutically acceptable salts thereof which are useful as antispasmodic agents. This is a continuationin-part of our copending application, S. N. 643,480, filed January 25, 1946, now abandoned.

These esters have the formula where R is an alkyl group of 4-6 carbon atoms, Y is an'alkylene bridge having at least two carbon atoms separating the oxygen and nitrogen atoms, and N=B is a tertiary-amino group wherein B represents two alkyl groups or the atoms necessary to complete a heterocyclic ring. More specifically Y may be a divalent hydrocarbon radical such as ethylene, propylene, butylene, l-methylethylene, 2-methylethylene or l-methylbutylene; and N=B includes such structures as dimethylamino, ethylmethylamino, diethylamino, dipropylamino, dibutylamino, butylpropylamino, piperidyl, 2-methylpiperidyl, morpholinyl, thiomorpholinyl, betahydroxyethylethylamino, etc. These may be classed together as aliphatic tertiary-amino groups; the heterocyclic rings are distinctly non-aromatic in character and can be thought of as two alkyl groups joined together by a divalent bridge such as CH2--, O- or --S.

These compounds are generally used in the form of water-soluble acid-addition salts or quaternary ammonium derivatives. The acids which may be used to prepare the salts are those which produce, when combined with the basic esters, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that the beneficial physiological properties inherent in the basic esters are not vitiated by side-efiects ascribable to the anions. Appropriate acid addition salts are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, and sulfuric acid; and organic acids such as acetic acid, citric acid and tartaric acid. The quaternary am- I monium derivatives are obtained by the addition of alkyl or aralkyl esters of inorganic acids or organic sulfonic acids, such as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, benzyl chloride, benzyl bromide, methyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, etc.

Synthetic antispasmodics usually have both a musculotropic (papaverine-like) action and neurotropic (atropine-like) action. It is desirable that new compounds be introduced which have high neurotropic activity but which lack the characteristic undesirable physiological sideeffects' of ,atropine.

Our' compounds are distinguished by high neurotropic activity, and, in addition, several members of the series show antihistaminic action.

Our compounds are conveniently prepared by esterification of the corresponding substituted acetic acid, (C5H9)CHR-COOH. The acids themselves are prepared in the following general manner. The sodio derivative of diethyl cyclopentylmalonate, (CsHg)CH(COOC2H5)z, is alkylated with RX, where R is an alkyl group of 4-6 carbons and X is a halogen atom; i. e. chlorine, bromine or iodine. The resulting cyclopentylalkylmalonlc ester,

which involves preparation of the corresponding A-cyclopentenylalkylmalonic ester,

CsH'I-CR-(COOCzHs) 2 by alkylation of diethyl A' -cyclopentenylmalonate, followed by reduction of the double bond. This method is desirable because it provides intermediates for the basic esters of n -cyclopentenylalkylacetic acids which are also valuable compounds.

In some cases where the malonic esters are difllcult to prepare because of the steric hindrance of the groups involved, an alternative procedure can be used. This is based on the method of Alexander and Cope [J. Am. Chem. Soc. 66, 886 (1944)], which involves condensation of an aidehyde or ketone with ethyl cyanoacetate and reduction of the resulting ethylenic double bond, all carried out in one step. In preparing the compounds of the present invention the carbonyl compound used has a structure such that the group R in the resulting substituted cyanoacetic ester, R-CH(CN)-COOC2H5, has 46 carbon atoms. For example, condensation of ethyl cyanoacetate and methyl isopropyl ketone in the presence of ammonium acetate, acetic acid and palladium-on-charcoal in an atmosphere of hydrogen gives ethyl (1,2-dimethylpropyl) -cyanoacetate. The sodio-derivative of the mono-substituted cyanoacetic ester is then alkylated with a cyclopentylhalide to give an ethyl cyclopentylalkylcyanoacetate, (Cal-I9) CR (CN) COOC2H5. This ishydrolyzed and decarboxylated to the corresponding cyclopentylalkylacetic acid,

(CsHs) -CHRCOOH although in lower yield than the hydrolysis and decarboxylation of the corresponding malonic ester. Substituted acetamides appear as byproducts and more drastic conditions of hydrolysis lead to decomposition. Again, in many instances we prefer to prepare first a n -cyclopentenylalkylcyanoacetate by alkylation of a mono-substituted cyanoacetic ester with a A -cyclopentenylhalide, followed by reduction of the ring double bond to a cyclopentylalkylcyanoacetate. Although one step longer, this process provides intermediates for the preparation of valuable basic esters of A -cyclopentenylalkylacetic acids as well as those of the present invention.

The preferred method, the malonic ester or cyanoacetic ester synthesis, in a given case depends upon the nature of the alkyl group to be introduced. If the allryl group to be introduced is of the straight chain type or is branched at the end, the malonic ester synthesis is preferred. If the alkyl group is branched, particularly near its point of juncture with the rest of the molecule, the cyanoacetic ester method is preferred.

The esters of our invention, having the general formula CH9CH(R)COOYN=B as described above, and their acid addition salts, are prepared from the free acid by one of the following methods:

(1) An acid halide 0r anhydride of a cyclopentylalkylacetic acid is reacted with a tertiaryaminoalkanol of the formula HO-YN=B, where Y is an alkylene bridge of at least 2 carbon atoms and N=B is a tertiary-amino group. The reaction is efiected by simple admixture of the two components although heating is generally used to accelerate the reaction. The free basic a 4 ester is obtained by addition of alkali to the reaction mixture. The basic ester may be converted to an acid addition salt by the addition, preferably in non-aqueous medium, of a therapeutically acceptable acid, such as hydrogen chloride in alcoholic solution.

(2) The cyclopentylalkylacetic acid is reacted with a tertiary-aminoalkanol using a mineral acid, such as sulfuric acid, as a catalyst, present in an amount greater than that necessary to neutralize the amino alcohol. The free basic ester and its acid addition salts are obtained as in method 1.

(3) The cyclopentylalkylacetic acid is heated with a tertiary-aminoalkyl halide of the formula ZY-N=B, where Z is halogen (preferably chlorine or bromine) and Y and B have the same meaning as before. The free basic esterand its acid addition salts are obtained as in meth- Od 1.

(4) A metallic salt of a cyclopentylalltylacetic acid is heated or simply mixed with afitertiaryaminoalkyl halide. In this case the }'free basic ester is formed directly.

Quaternary ammonium salts are prepared by mixing the free basic ester with a lower alkyl or aralkyl ester of a strong inorganic acid or organic sulfonic acid, preferably in an inert organic solvent such as benzene or ether, with or without gentle heating. The salt either crystallizes immediately or can be obtained by concentration of the solvent.

EXAMPLE 1 (a) Diethyl A -cyclopentenyl-isobutlumalonate. To a stirred suspension of 27.6 g. (1.2 m.) of powered sodium in 240 cc. of dry toluene is slowly added 271.6 g. (1.2 m.) of diethyl A -cyclopentenylmalonate. [Noller and Adams, J. Am. Chem. Soc. 48, 2444 (1926).] After nearly all of the sodium has reacted at reflux temperature, 210 g. (1.5 m.) of isobutyl bromide is added dropwise and the mixture refluxed for sixteen hours. After cooling, the mixture is neutralized with dilute acetic acid, and the toluene layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is distilled at reduced pressure, first through a Claisen head and then redistilled through an eificient fractionating column. After discarding considerable low boiling material, the product distils at 73 C. (0.02 mm.) giving about 145 g. (46%) of diethyl n -cyclopentenyl-isobutylmalonate,

n =1.4580, d4 =l.0157

(b) Diethyl cycZopentyl-isobutylmalonate.-A

solution of 77.7 g. (0.275 m.) of diethyl A -cycIopentenyl-isobutylmalonate in 30 cc. of alcohol is hydrogenated in the presence of 0.2 g. of Adams platinum oxide catalyst at about 50 pounds pressure. Reduction is complete in about one hour. The product is recovered and distilled at. reduced pressure through a Claisen head, giving about 76 g. (98%) of diethyl cyclopentyl-isobutylmalonate, B. P. 96 C. (0.04 mm.) n =1.4532; d4 =1.0023.

(c) Cyclopentyl-isobutylacetic acid.--A mixture of 1160 g. of diethyl cyclopentyl-isobutylmalonate with a solution of 1000 g. of potassium hydroxide in 2500 cc. of ethanol is heated in a bomb at -150 C. for three hours. After cooling, most of the alcohol is distilled off, water is added to the residue and the whole neutralized with hydrochloric acid. The substituted acetic acid is extracted with ether, and the ether extracts are washed with water and with saturated carbon dioxide ceases to be evolved. Distilla:

tion at reduced pressure gives about 810 g. (97%) of cyclopentyl-isobutylacetic acid, B. P. 79-82 C. (0.08 mm.); n =1.4549; d4 =0.9525.

(d) Beta-diethylaminoethyl cyclOpentyl-isobutylacetate and its hydrochloride.-Cyclopentylisobutylacetic acid (19 g., 0.103 m.) is neutralized to phenolphthalein with alcoholic sodium ethoxide, and 13.9 g. (0.103 m.) of beta-diethylaminoethyl chloride in 40 cc. of isopropyl' alcohol is then added. After standing for several days (or,

refluxing for several hours), the sodium chloride is removed by filtration, and the volatile solvents are distilled off. The basic ester is dissolved in etherfwashed with water and extracted with cold dilute hydrochloric acid. The acid solution is washed with ether and made basic with sodium carbonate. The liberated basic ester is extracted with ether and the ether solution dried over anhydrous sodium sulfate. Distillation of the product at reduced pressure after removal of the ether gives about 20 g. (68%) of beta-diethylaminoethyl cyclopentyl isobutylacetate, B. P. 113 C. (0.03, mm.); n =1.4527; d4 =0.9119.

The hydrochloride of beta-diethylaminoethyl cyclopentyl-isobutylacetate is prepared by passin hydrogen chloride gas into a solution of 18 g. of the free basic ester in absolute ether. A colloidal precipitate forms which crystallizes upon stirring. After filtering, washing with ether and drying, the hydrochloride is obtained, 19.2 g. (94%) M. P. 1185-1195 C.

EXAMPLE 2 (a) Cyclopentyl-isobutylacetyl chloride.-A mixture of 814 g. (4.42 m.) of cyclopentyl-isobutylacetic acid (see Example 1 for preparation of this acid) and 726 cc. of technical grade thionyl chloride is heated on a steam bath until gas ceases to be evolved. The excess thionyl chloride is removed by distillation and the product is distilled from a Claisen flask giving about 866 g. (96.5%) of cyclopentyl-isobutylacetyl chloride, B. P. 99 C. (6 mm), n =1.4608;

(b) Beta-(N-piperidyl) -ethyl cyclopentyl-isobutylacetate and its hydrochloride.Beta-(N- piperidyl)-ethy1 alcohol (19.2 g., 0.148 m.) is dissolved in 100 cc. of dry pyridine and 30 g. (0.148 m.) of cyclopentyl-isobutylacetyl chloride is added, and the mixture is allowed to stand for a few minutes and finally heated on a steam bath for four hours. After cooling the mixture, it is shaken with a solution of 12 g. of sodium carbonate monohydrate in 250 cc. of water and the water layer is separated and extracted with ether. The combined organic layers are concentrated using a water aspirator and the residue distilled at reduced pressure, giving about 3'7 g. (85%) of beta-(N-piperidyl) -ethyl cyclopentyl-isobutylacetate, B. P. 106-108 C. (0.02 mm.); n =1.4717; d =0.9600.

The hydrochloride is prepared by passing dry hydrogen chloride gas into a solution of 34 g. (0.115 m.) of ,the free basic-ester in 500 cc. of anhydrous ether. A white, crystalline precipitate forms which is filtered and dried giving about 31 g. (82%) of the hydrochloride of beta-(N-piperidyl) -ethyl cyclopentyl-isobutylacetate, M. P. 177.5180 C.

made basic with sodium hydroxide.

EXAMPLE 3 Beta (N-beta-hydromyethyl-N-ethylamino) ethyl cyclopentyl-isobutylacetate and its hydrochl0ride.To a solution of 13.3 g. (0.1 m.) of N- talline precipitate separates. After several hourson a steam bath, the solvent is removed, the residue dissolved in dilute hydrochloric .acid, and the solution is extracted twice with ether and The product is extracted with ether, washed with saturated sodium chloride solution and .dried over anhydrous sodium sulfate. After removal of the ether, the product is distilled at reduced pressure from a 50 cc. Claisen flask containing a 6fractionating column packed with helices. The main fraction boils at 106" C. (0.012 mm.) giving about 14.2 g. (43%) of beta-(N-beta-hydroxyethyl-N-ethylamino) -ethyl cyclopentyl-isobutylacetate; n =1.4653; d =0.9706.

The hydrochloride is prepared in the usual manner by passing dry hydrogen chloride gas through a solution of the basic-ester in anhydrous ether. The dry, crystalline, hygroscopic product has the M. P. 59-62 C.

EXAMPLE 4 temperature and 50 pounds pressure. Reduction is complete in about one hour. Five such runs are combined, filtered, and the solvent is removed in vacuo on a steam bath. The residue is taken up in ether, washed with water, sodium bicarbonate solution and saturated salt solution, and dried over anhydrous sodium sulfate. After removing the solvent, the product is distilled twice at reduced pressure from a Claisen flask and then through an efficient fractionating column, giving about 143 g. (31%) of nearly colorless ethyl (1,2- dimethylpropyl)-cyanoacetate. B. P. 60 C. (0.12 mm.); n =l.4322; d =0.9552.

(b) Ethyl A cyclopentenyl (LZ-dimethylpropyl)-cyanoacetate.-To 11.5 g. (0.5 m.) of sodium melted under cc. of dry toluene in a 1 liter flask, is slowly added (with vigorous stirring) 91.5 g. (0.5 m.) of ethyl (l,2-dimethylpropyl)- cyanoacetate. When practically all of the sodium has reacted, '77 g. (0.75 m.) of A -cyclopenteny1 chloride is added. Sodium chloride separates and the reaction mixture tests acidic almost immediately. Water is added, the layers separated, and the aqueous layer is extracted with ether. The combined organic layers are washed with saturated sodium chloride solution, and the solvert is removed in vacuo. The residue is distilled at reduced pressure, first from a Claisen flask and then through an efficient fractionating column, giving about 84 g. (67%) of yellow ethyl Li -cyclopentenyl-(1,2-dimethylpropyl) -cyanoacetate, B. P. 84 C. (0.07 mm.); n :1.4709; d =0.9974.

(c) Ethyl cyclopentyl (LZ-dimethylpropybcyanoacetate.A solution of 44.8 g. (0.18 m.) of ethyl A cyclopentenyl (1,2-dimethylpropyD- cyanoacetate in 100 cc. of ethanol is hydrogenated at 50 pounds pressure and 30 C. with 0.2 g. of platinum oxide catalyst. The theoretical amount of hydrogen is absorbed in one hour, and, after filtering, the solvent is removed and the product is distilled at reduced pressure, giving about 40 g. (88.5%) of ethyl cyclopentyl-(1,2-dimethylpropyD-cyanoacetate, B. P. 76 C. (0.01 mm.); n =1.4637; d,= =0.9850.

(d) C'yclopentyl (LZ-dimethylpropyl)-acetic acid.-A mixture 01' 38.7 g. (0.154 m.) or ethyl cyclopentyl (1,2-dimethylpropyl) -cyanoacetate with a solution of 75 g. of potassium hydroxide in 125 cc. of 90% ethanol is heated in a bomb in an oil bath at 160-180 C. for 42 hours. After cooling, the contents of the bomb are diluted with water and a crystalline neutral fraction [cyclopentyl-(1,2-dimethylpropyl) -acetamidel is filtered off. The filtrate is acidified and the acidic oil is extracted with ether, washed three times with water and once with saturated sodium chloride solution containing a little sodium bicarbonate. and finally dried over anhydrous sodium sulfate. After removal of the solvent, the

product is distilled at reduced pressure from a Claisen flask giving about 9.7 g. (32%) of cyclopentyl-(1,2-dimethylpropyl)-acetic acid, B. P. 96 C. (0.06 mm.) n =1.4651; d =0.9668.

(e) Beta-diethylaminoethyl cyclopentyl-(1,2- dimethylpropyl) -acetate and its hydrochloride.- This is prepared from the substituted acetic acid using sodium ethoxide and beta-diethylaminoethyl chloride according to the method shown in Example 1, part (d). Eight and three-tenths grams of the acid results in about 8.4 g. (67%) of beta-diethylaminoethyl cyclopentyl-(1,2-dimethylpropyD-acetate, B. P. 108 C. (0.06 mm.); n =1.4601; d =0.9272.

The hydrochloride is prepared in the usual manner from the basic-ester and dry hydrogen chloride gas in either solution. The crude product is recrystallized from methyl isobutyl ketone giving about a 69% yield of hydrochloride, M. P. 141-146 C.

.EXAMPI5E5 (a) Ethyl A -cyclopentenyl- (l-methylbutyvcyanoacetata-To 18.4 g. (0.8 m.) of sodium melted under 180 cc. of dry toluene in a 1 liter flask, is slowly added (with vigorous stirring) 124 g. (0.8 m.) of ethyl (l-methylbutyD-cyanoacetate [Alexander and Cope, J. Am. Chem. Soc. 66, 886 (1944)]. When practically all of the sodium has reacted, 123 g. (1.2 m.) of A -cyclopentenyl chloride is added. Sodium chloride separates and the reaction mixture tests acidic almost immediately. Water is added, the layers are separated and the aqueous layer is extracted with ether. The organic layer is washed with saturated sodium chloride solution and the solvent is removed at reduced pressure. The product is distilled at reduced pressure, first from a Claisen flask and then through an efllcient column, giving about 125 g. (63%) of ethyl A cyclopentenyll-methylbutyl) cyanoacetate,

B. P. 95 C. (0.2 mm.); n =1.4678; d4 =0.9893. 0 R

(b) Ethyl cyclopentyl- KI-methyZbutyU-cyanoacetate.-A solution of 62.4 g. (0.25 m.) of ethyl A -cyclopentenyl-(l-methylbutyl) cyanoacetate in 100 cc. of ethanol is hydrogenated at room temperature and 50 pounds pressure using 0.2 65

flask, giving about 62 g. (98%) of ethyl cyclo- 70 pentyl-(l-methylbutyl)-cyanoacetate, B. P. 95 C. (0.27 mm.); n =1.4606; d4 =0.9762.

(c) Cyclopentyl- (1 -methylbutyl) -acetic acid.- A mixture of g. of ethyl cyclopentyl- (l-methylbutyl) -cyanoacetate with a solution of 75 5 precipitate separates which is collected, washed with water and dried; weight, 11 g. (35%). This proves to be cyclopentyl-(l-methylbutyl)-acetamide, and a sample when recrystallized from hexane melts at 94-109 C. The basic aqueous b filtrate from above is extracted with ether and then acidified with hydrochloric acid. The product is recovered and purified as in Example 1, part 0 giving about 11 g. (35%) 0t cyclopentyl- (l-methylbutyD-acetic acid. B. P. 96 C. (0.07 15 mm.); n =1.4623; d4 =0.9591.

(d) Beta-diethylaminoethul I cyclopentill-(lmethylbutyl) -acetate and its hudrochloride. Cyclopentyl-isobutylacetic acid (11 g., 0.055 m.) is neutralized to phenolphthalein with alcoholic sodium ethoxide, and 7.5 g. (0.055 m.) of betadiethylaminoethyl chloride in 25 cc. of isopropyl alcohol is then added. After standing for several days (or refluxing for several hours), the sodium chloride is removed by filtration, and the volatile 25 solvents are distilled off. The basic ester is dissolved in ether, washed with water and extracted with cold dilute hydrochloric acid. The acid solution is washed with ether and made basic with sodium carbonate. The liberated basic 3O ester is extracted with ether and the ether solu- 40 of 9.5 g. of the basic ester in absolute ether. A

crystalline precipitate forms which is filtered, washed with ether and dried, giving about 6.9 g. o! the hydrochloride. When recrystallized from methyl isobutyl ketone it melts at 99-103 C. Y

Additional compounds have been made by the methods outlined in the preceding examples and are disclosed in the following tables:

A. M alonates B. P. 0. ([1 mm.) no" usages 11 p 12 TABLE III-Continued Basic Bunk-Continued B P a Com a Y-N=B (D in) cmcmcn omoncm- -cmon we a on H: CHaCHl Onion] n cumin -cmcn 101 o in) CHICK.

. CBQCH. 1 cmcmcn- -cmcn 1100114) 5 CHICK] CHI s........ cmcmcn- -cmcH,N (our!) e CH:

CHECK! 0.-.... CH|(CH|)|- -on.cn 10s a m) omen;

. CHsCH m cmcn-cn- -cmca 108 (0.00)

4 Ha Bl aCHI CIhCHu 11...... cmcmcmcn- -cn.cn,N m (0.35)

HI CHaCH:

CHaCH;

12...---- CHICHCHJCHF CH;C 83 (0. 025) He HaCH:

CHQCH] 1s....... cn cmcncnr- -cn,cm 97 o. 02)

Ha CHsCH:

omen

14....... CHsCHaCHCHg- CH|CH 95 (0. 005) on. n. omenmorpholinyl radicals; and acid addition and Hydro hlorid 5 quaternary ammonium salts thereof. 2. A substance or the group consisting oi basic esters of the formula 0.0110 mas-119.5 0.9204 111 114.5 0.9548

a 019166 101 -1os 0.9193 115 -11s i 0.9402 105 409 0. 9118 103. 5-105 0.9272 141 l46 38 1 5 wherein R is an alkyl group of 4-6 carbon atoms, 31 116 I Y is an alkylene bridge of 2-5 carbon atoms and 0-9176 111-5413 R and R" are lower alkyl groups; and acid addition and quaternary ammonium salts thereof. We claim: I 3. A substance of the group consisting of basic 1. A substance of the group consisting of basic esters of the formula esters of the formula a, a

' /CHr-CH!\ on coo Y N CHC0OY-N\ cm BB is cm-cm wherein R is an alkyl group of 4-6 carbon atoms, Y is an aikylen'e bridge of 2-5 carbon atoms and -N=B is a tertiary-amino group of the class consisting of di-lower-alkylamino, piperidyl and 4. A substance of the group consisting of the formula R omen;

wherein R is an alkyl group of 4-6 carbon atoms, and acid addition and quaternary ammonium salts thereof. 4

5. A substance of the group consisting of betadiethylaminoethyl cyclopentyl n butylacetate of the formula CHzCHa CH-C O CHzCHzN zCHzCHzCH: CHzCH;

and acid addition and quaternary ammonium salts thereof.

6. A substance of the group consisting of beta- (N-piperidyl) -ethyl cyclopentyl isobutylacetate of the formula CHzCHz CH-OOOCHzCH: CH2

HzCHCHs CHZC i and acid addition and quaternary ammonium salts thereof.

7. A substance of the group consisting of betadiethylaminoethyl cyclopentyl (2 ethylbutyl) acetate of the formula CHiCHa CHC O OCHzCHaN CHzCHCHzCHz CHzCH:

CHzCH:

and acid addition and quaternary ammonium salts thereof.

8. A substance of the group consisting of betadiethylaminoethyl cyclopentyl-isobutylacetate of the formula CHzCHa cn-coocmomn k mono-m onion,

and acid addition and quaternary ammonium salts thereof.

9. A substance of the group consisting of betadimethylaminoethyl cyclopentyl sec.-butylacetate of the formula cc-cooomcam ,Homcm cm and acid addition and quaternary ammonium salts thereof.

- ROBERT BRUCE MOFFE'I'I.

CHARLOTTE ANNE HART.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Yohe et 91.. Chem. Abstracts, vol. 22 (1928), pp. 2147-2148.

Adams, Chem. Abstracts, vol. 23 (1929), page 3543.

Certificate of Correction Patent No. 2,538,793 January 23, 1951 ROBERT BRUCE MOFFETT ET AL. ,It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:

Column 4, line 35, for -i sobutlymalonate read -v lsobutylmalonate; column 7, line 36, for the word either read ether; columns 11 and 12, Table III, under the heading YN=B, opposite compound 5?, for

OHQHICH CHQCHflOH CH1CH; I read CH| Ha CHa I CHzCHl line 61, opposite compound 13, for 116477 read 116-117; column 13, line 1, after of, second occurrence, insert a cmnpoumd of; column 14, line 14,

for that portion of the formula reading CCCOOCH CH N read and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Ofiice.

Signed and sealed this 10th day of April, A. D. 1951.

' THOMAS F. MURPHY, I

I Assistant Oommz'asioner of Patents. 

1. A SUBSTANCE OF THE GROUP CONSISTING OF BASIC ESTERS OF THE FORMULA 